The vagus nerve and the inflammatory reflex--linking immunity and metabolism

Abstract

The vagus nerve has an important role in regulation of metabolic homeostasis, and efferent vagus nerve-mediated cholinergic signalling controls immune function and proinflammatory responses via the inflammatory reflex. Dysregulation of metabolism and immune function in obesity are associated with chronic inflammation, a critical step in the pathogenesis of insulin resistance and type 2 diabetes mellitus. Cholinergic mechanisms within the inflammatory reflex have, in the past 2 years, been implicated in attenuating obesity-related inflammation and metabolic complications. This knowledge has led to the exploration of novel therapeutic approaches in the treatment of obesity-related disorders.

Figure 1

The functional anatomy of the inflammatory reflex. Inflammatory mediators, such as cytokines, are released by activated macrophages and other immune cells when TLRs and NLRs are activated upon immune challenge. These mediators are detected by sensory components of the afferent arm of the inflammatory reflex (red). Neuronal interconnections between the NTS, A P, DMN, NA, and higher forebrain regions (not shown) integrate afferent signalling and efferent vagus nerve-mediated immunoregulatory output. Efferent vagus nerve cholinergic output to the spleen, liver and gastrointestinal tract (blue) regulates immune activation and suppresses proinflammatory cytokine release (dotted red lines). This efferent cholinergic arm of the inflammatory reflex can be activated in the brain through mAChR-mediated mechanisms triggered by mAChR ligands and AChE inhibitors, such as galantamine. Abbreviations: AChE, acetylcholinesterase; A P, area postrema; DMN, dorsal motor nucleus of the vagus nerve; LPS, lipopolysaccharide (endotoxin); mAChR, muscarinic acetylcholine receptor; NA, nucleus ambiguus; NLRs, nucleotide-binding oligomerization domain-like receptors; NTS, nucleus tractus solitarius; TLR4, toll-like receptor 4.

Figure 2

Molecular mechanisms of cholinergic control of inflammation. Efferent vagus nerve activity is translated into catecholamine-mediated activation of T-cell-derived acetylcholine release in the spleen and into direct acetylcholine release from efferent vagus nerve endings in other organs. Inhibition of NF-κB nuclear translocation and activation of a JAK2-STAT3-mediated signalling cascade in macrophages and other immune cells are implicated in cholinergic α7nAChR-mediated control of proinflammatory cytokine production. Abbreviations: ACh, acetylcholine; β₂AR, β₂ adrenergic receptor; JAK2, Janus kinase 2; α7nAChR, α 7 nicotinic acetylcholine receptor; NA, noradrenaline; NF-κB, nuclear factor κB; STAT3, signal transducer and activator of transcription 3.

Figure 3

The role of the vagus nerve in metabolic regulation. Gastrointestinal and hepatic vagus nerve afferents (red) communicate alterations in peripheral levels of micronutrients and metabolic molecules to the brain. Neural interaction between the interconnected NTS, DMN and A P, within the dorsal vagal complex, and reciprocal projections between this brainstem region and several hypothalamic areas (arcuate and paraventricular nuclei and mediobasal and lateral areas), underlie brain integration of visceral information and the modulation of efferent motor vagus nerve output, leading to regulation of metabolic homeostasis. Efferent vagus nerve signalling (blue) can be triggered by sensing metabolic alterations in the brainstem and the hypothalamus. Complex communication between hypothalamic nuclei and other forebrain structures (such as the insula and premotor cortex, amygdala, nucleus accumbens, parabrachial nucleus and thalamus) mediate hedonic, motivational and rewarding aspects of feeding behaviour and their interaction with vagus nerve-mediated homeostatic mechanisms. Abbreviations: A P, area postrema; CCK, cholecystokinin; DMN, dorsal motor nucleus of the vagus nerve; GLP-1, glucagon-like peptide-1; NA, nucleus ambiguus; NTS, nucleus tractus solitarius; PYY, peptide YY.

Figure 4

Possible therapies based on cholinergic-based approaches for the treatment of obesity-driven disorders. Obesity progression and the metabolic syndrome are closely associated with debilitating diseases, including T2DM, CVD and NASH. Dysregulated immune and metabolic homeostasis is associated with inflammation underlying obesity-related disease pathogenesis, which mediates insulin resistance and other complications. Efficacy of cholinergic agents in activating regulatory mechanisms in the inflammatory reflex in animals indicates a rationale for developing novel treatments for humans. Cholinergic therapeutics and devices for vagus nerve stimulation could selectively control the complex interplay between immune and metabolic pathways. Abbreviations: CVD, cardiovascular disease; M3 mAChR, M3 muscarinic acetylcholine receptor; α7nAChR, α7 nicotinic acetylcholine receptor; α4/β2nAChR, α4/β2 nicotinic acetylcholine receptor; α3/β4nAChR, α3/β4 nicotinic acetylcholine receptor; NASH, nonalcoholic steatohepatitis; T2DM, type 2 diabetes mellitus; VNS, vagus nerve stimulation.